The present invention relates to nociceptin receptor ORL-1 agonist 8-(bis-(halophenyl) methyl)-3-heteroaryl-8-azabicyclo-[3.2.1]octan-3-ols and derivatives thereof useful in treating cough, pain, anxiety, asthma, alcohol abuse or depression. Pharmaceutical compositions comprising the compounds and combinations of the claimed compounds with other agents for treating cough, allergy or asthma symptoms are also disclosed.
8-(bis-(halophenyl)methyl)-3-heteroaryl-8-azabicyclo-[3.2.1]octan-3-ols were generically, but not specifically, disclosed in U.S. Pat. No. 6,262,066 B1 and WO 01/07050 as being useful in the treatment of cough, pain, anxiety, asthma, alcohol abuse or depression. Compounds of the present invention represent a selection invention over U.S. Pat. No. 6,262,066 B1 and WO 01/07050.
Compounds of the present invention are represented by formula I 
or pharmaceutically acceptable salts thereof, wherein
R is R4-heteroaryl or 
R1 is H or C1-C6 alkyl;
R2 and R3 are independently selected from the group consisting of xe2x80x94CH3, xe2x80x94OCH3, fluoro, chloro, bromo and iodo;
R4 is 1 to 4 substituents independently selected from the group consisting of H, halo, (C1-C6) alkyl, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94(CH2)nxe2x80x94OR5, xe2x80x94(CH2)nxe2x80x94NR5R6, xe2x80x94(CH2)nxe2x80x94NHSO2R5, xe2x80x94(CH2)nxe2x80x94NH(CH2)2NR5R6, xe2x80x94(CH2)nxe2x80x94NHC(O)NR5R7, xe2x80x94(CH2)nxe2x80x94NH(CH2)2OR5 and 1-piperazinyl;
n is 0, 1, 2 or 3;
R5 and R6 are independently selected from the group consisting of H and C1-C-3 alkyl; and
R7 is H, C1-C-3 alkyl or amino(C1-C-3)alkyl.
In another aspect, the invention relates to a pharmaceutical composition comprising at least one compound of formula I and a pharmaceutically acceptable carrier.
The compounds of the present invention are agonists of the ORL-1 receptor, and therefore, in another aspect, the invention relates to a method of treating pain, anxiety, cough, asthma, alcohol abuse or depression, comprising administering to a mammal in need of such treatment an effective amount of at least one compound of formula I.
In another aspect, the invention relates to a method of treating cough, comprising administering to a mammal in need of such treatment: (a) an effective amount of at least one compound of formula I; and (b) an effective amount of one or more additional agents for treating cough, allergy or asthma symptoms selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, xcex2-adrenergic receptor agonists, xanthine derivatives, xcex1-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists.
In still another aspect, the invention relates to a pharmaceutical composition comprising at least one compound of formula I and one or more additional agents selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, xcex2-adrenergic receptor agonists, xanthine derivatives, xcex1-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists.
Referring to formula I, above, preferred compounds of the invention are those wherein R2 and R3 are in the 2-position on the phenyl rings. Also preferred are compounds wherein the same halo atom is selected for each of R2 and R3. More preferred are compounds wherein R2 is chloro and R3 is chloro, with compounds wherein R2 is 2-chloro and R3 is 2-chloro being most preferred.
Also preferred are compounds wherein R is R4-heteroaryl wherein heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl or indolyl, in particular 2-pyridyl or 2-pyrimidinyl. Preferred definitions of R4 are hydrogen, (C1-C6) alkyl, xe2x80x94OR5 and 1-piperazinyl. More preferred definitions of R are 2-pyrimidinyl, 5-ethyl-2 pyrimidinyl, 4-(1-piperazinyl)-2-pyrimidinyl, 2-pyridyl and 6-methoxy-2-pyridyl.
R1 is preferably H or xe2x80x94CH3, with H being more preferred.
The following individual compounds are especially preferred: 
A preferred indication for compounds of formula I is for the treatment of cough.
As used herein, the following terms are used as defined below unless otherwise indicated:
halo represents fluoro, chloro, bromo and iodo;
heteroaryl represents cyclic aromatic groups of 5 or 6 atoms or bicyclic groups of 9 to 10 atoms having 1, 2 or 3 heteroatoms independently selected from O, S or N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, provided that the rings do not contain adjacent oxygen and/or sulfur atoms. Nitrogen atoms can form an N-oxide. All regioisomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. Typical 6-membered heteroaryl groups are pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the N-oxides thereof. Typical 5-membered heteroaryl rings are furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl and isoxazolyl. Bicyclic groups typically are benzo-fused ring systems derived from the heteroaryl groups named above, e.g. quinolyl, phthalazinyl, quinazolinyl, benzofuranyl, benzothienyl and indolyl. The heteroaryl ring can be substituted with 1-4 R4 groups, wherein any of the available substitutable carbon or nitrogen atoms in said heteroaryl group may be optionally and independently substituted.
Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers). The invention contemplates all such stereoisomers both in pure form and in mixture, including racemic mixtures.
Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of the invention can be prepared by known methods from starting materials either known in the art or prepared by methods known in the art.
A typical method for preparing the compounds of formula Ia wherein R1 is H comprises reacting an 8-[bis-(halophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-one of formula II with a lithium derivative of a heteroaryl: 
The starting material of formula II can be prepared according to the following reaction scheme: 
The compound of formula II can be prepared by alkylation of piperidine derivative III with diphenyl-bromomethane derivative IV in the presence of a base such as K2CO3, in a solvent such as CH3CN, at 80xc2x0 C. Compounds of formulas III and IV are known or can be prepared by known methods.
Compounds of the present invention and preparative starting materials thereof exemplified below should not be construed as limiting the scope of the disclosure.
The following solvents and reagents are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); ethyl acetate (EtOAc); lithium diisopropyl amide (LDA); triethylamine (Et3N) and N,N-dimethylformamide (DMF). Room temperature is abbreviated as RT.

Add xcex1-chloroethyl chloroformate (15.4 g, 108 mmol) to a solution of tropinone (10 g, 71.84 mmol) in dichloroethane (200 ml) dropwise at 0xc2x0 C. Heat the reaction to reflux for 2 h. Evaporate the solvent to produce a brown residue. Dissolve the residue in MeOH (200 ml) and heat it to reflux for 2 h. Evaporate the MeOH and stir the solid in EtOAc, filter, collect the solid and wash with ether to give the product (7 g). Crude product was used without further purification. 1H NMR (CDCl3) xcex44.45 (s, br, 2H), 3.35 (dd, 2H), 2.58 (d, 2H), 2.49 (dd, 2H), 2.0 (m, 2H).

Step 1:
Add NaBH4 (1.5 g, 39.82 mmol) to a solution of 2,2xe2x80x2-dichlorobenzophenone (5 g, 19.9 mmol) in MeOH (40 ml) at RT and stir for 2 h. Quench the reaction with H2O, neutralize with 1N HCl and remove the MeOH. Extract the residue with EtOAc, wash with brine, dry over MgSO4 and concentrate to give the desired compound (5 g) as white solid, which was used for next step reaction without purification. 1H NMR (CDCl3) xcex47.45 (m, 4H), 7.35 (m, 4H), 6.60 (d, 1H), 2.58 (d, 1H, OH).
Step 2:
Treat the product of Step 1 (20.36 g, 80.47 mmol) in CH2Cl2 with SOBr2 (30.11 g, 144.85 mmol) at 0xc2x0 C. and stir it at RT overnight. Quench the reaction with ice and NaHCO3 (aq), extract with CH2Cl2, dry and filter. Remove the solvent to produce the desired bromide (23.6 g). 1H NMR (CDCl3) xcex47.6 (d, 2H), 7.4 (d, 2H), 7.13 (m, 4H), 7.0 (s, 1H).

Heat a mixture of the products from Preparation 1 (26 g, 161 mmol) and Preparation 2 (53 g, 168 mmol) and K2CO3 (110 g, 796 mmol) in anhydrous CH3CN (410 ml) to 80xc2x0 C. for 80 h. Cool the reaction mixture to RT and filter. Evaporate the solvent and purify the solid by flash column chromatography (4%, 7% EtOAc/Hexane) to obtain the desired compound. 1H NMR (CDCl3) xcex47.9 (d, 2H), 7.3 (m, 4H), 7.2 (m, 2H), 5.7 (s,1H), 3.35 (s, br, 2H), 2.7 (dd, 2H), 2.3 (m, 2H), 2.2 (d, 2H), 1.65 (dd, 2H).